US6034090A - 1-Phenylalkyl-1,2,3,6-tetrahydropyridines for treating Alzheimer's disease - Google Patents
1-Phenylalkyl-1,2,3,6-tetrahydropyridines for treating Alzheimer's disease Download PDFInfo
- Publication number
- US6034090A US6034090A US09/331,006 US33100699A US6034090A US 6034090 A US6034090 A US 6034090A US 33100699 A US33100699 A US 33100699A US 6034090 A US6034090 A US 6034090A
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- United States
- Prior art keywords
- alkyl
- group
- compound
- formula
- alkoxy
- Prior art date
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- Expired - Fee Related
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Definitions
- the present invention relates to novel 4-substituted 1-phenylalkyl-1,2,3,6-tetrahydropyridines with neurotrophic and neuroprotective activity, to a method of preparing them and to pharmaceutical compositions containing them.
- EP-0 458 696 describes the use of a 1-(2-naphthylethyl)4-(3-trifluoro-methylphenyl)-1,2,3,6tetrahydropyridine for the preparation of drugs intended for the treatment of cerebral and neuronal disorders.
- the present invention therefore relates to the compounds of formula (I): ##STR1## in which: Y is --CH-- or --N--;
- X is:
- (C 1 -C 3 )alkyl denotes methyl, ethyl, n-propyl and i-propyl groups.
- alkoxy denotes a hydroxyl group substituted by a (C 1 -C 6 )alkyl, advantageously (C 1 -C 4 )alkyl and preferably (C 1 -C 3 )alkyl group.
- one preferred group is represented by the compounds in which the phenyl is substituted by 1 to 3 halogens, 1 to 3 CF 3 , 1 to 3 (C 1 -C 4 )alkyl, 1 to 3 (C 1 -C 4 )alkoxy, 1 to 3 cyano, 1 to 3 amino, 1 to 3 mono- or di-(C 1 -C 4 )alkylamino, 1 to 3 (C 1 -C 4 )-acylamino, 1 to 3 carboxyl, 1 to 3 (C 1 -C 4 )alkoxycarbonyl, 1 to 3 aminocarbonyl, 1 to 3 mono- or di-(C 1 -C 4 )alkylaminocarbonyl, 1 to 3 amino(C 1 -C 4 )alkyl, 1 to 3 hydroxy(C 1 -C 4 )alkyl or 1 to 3 halogeno(C 1 -C 4 )alkyl.
- Another preferred group consists of the compounds of formula (I) in which Y is a group --CH-- and R 1 is CF 3 .
- Particularly advantageous compounds are represented by formula (I'): ##STR4## in which R 1 ' is CF 3 and Y' is CH, or R 1 ' is Cl and Y' is N, R 2 and X being as defined above, and their salts, solvates and quaternary ammonium salts.
- Another preferred group consists of the compounds of formula (I') in which X is a (C 1 -C 6 )alkyl group.
- An aliphatic alcohol having from 1 to 6 carbon atoms such as methanol, ethanol, isopropanol, n-butanol or n-pentanol, is preferably used as the organic solvent, but it is also possible to use other solvents such as hexane, dimethyl-formamide, dimethyl sulfoxide, sulfolane, acetonitrile, pyridine and the like.
- the reaction temperature can vary between room temperature (about 20° C.) and the reflux temperature, the reaction times varying accordingly.
- the reaction has ended and the final product obtained can be isolated according to the conventional techniques in the form of the free base or one of its salts, the free base optionally being converted to one of its salts by simple salification in an organic solvent such as an alcohol, preferably ethanol or isopropanol, an ether such as 1,2-dimethoxyethane, ethyl acetate, acetone or a hydrocarbon like hexane.
- an organic solvent such as an alcohol, preferably ethanol or isopropanol, an ether such as 1,2-dimethoxyethane, ethyl acetate, acetone or a hydrocarbon like hexane.
- the starting amines of formula (II) in which Y is N can be prepared by reacting the appropriate 2-halogenopyridine of formula (p): ##STR7## in which R 1 is as defined above and Hal is a halogen atom, with a 1,2,3,6-tetrahydropyridine of formula (q): ##STR8## in which P o is a protecting group, for example the benzyl group, and Z is a substituent which allows the nucleophilic substitution of the pyridine halogen. Examples of such substituents are trialkylstannanes such as tributylstannane, or Grignard compounds.
- the neuroblasts are then inoculated at a rate of 17 ⁇ 10 4 cells/cm 2 into a non-serum culture medium consisting of DME/Ham's F12 medium containing selenium (30 nM) and transferrin (1.25 ⁇ M) in the wells of a titer plate. Each well has been treated with poly-L-lysine beforehand.
- the inoculated plates are placed in an incubator in the oven (37° C.; 5% CO 2 ).
- unit doses will normally be administered one or more times a day, for example 2, 3, 4 or 5 times a day and preferably one to three times a day, the overall dose in man varying between 0.5 and 1400 mg per day, advantageously between 1 and 900 mg per day, for example from 2 to 500 mg and more conveniently from 2 to 200 mg per day.
- the present invention relates to a pharmaceutical composition containing, as active principles, a compound of formula (I) and an M 1 receptor agonist or their pharmaceutically acceptable salts.
- NMDA receptor antagonist An example of an advantageous NMDA receptor antagonist is memantine (Arzneim. Forsch., 1991, 41, 773-780).
- the present invention also relates to a method of treating senile dementia of the Alzheimer type, which consists in administering, to a patient suffering from this disease, an effective dose of a compound of formula (I) or one of its pharmaceutically acceptable salts and an effective dose of a compound indicated in the symptomatic treatment of DAT, or one of its pharmaceutically acceptable salts, said compounds being administered simultaneously, sequentially or spread over a period of time and it being possible for the effective doses of the active principles to be contained in separate unit forms of administration; alternatively, if the two active principles are administered simultaneously, they are advantageously contained in a single pharmaceutical form.
- the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talcum, gum arabic or the like.
- a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talcum, gum arabic or the like.
- the tablets can be coated with sucrose or other appropriate substances or they can be treated so as to have a sustained or delayed activity and so as to release a predetermined amount of active principle continuously.
- a preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
- a preparation in the form of a syrup or elixir can contain the active ingredient together with a sweetener, which is preferably calorie-free, methyl-paraben and propylparaben as antiseptics, a flavoring and an appropriate color.
- a sweetener which is preferably calorie-free, methyl-paraben and propylparaben as antiseptics, a flavoring and an appropriate color.
- a mixture of 4.4 g (0.033 mol) of 3,4-diethylbenzene, 50 ml of methylene chloride and 8.8 g (0.044 mol) of bromoacetyl bromide is cooled to 0-5° C. and 5.0 g (0.037 mol) of aluminum trichloride are added.
- the mixture is stirred at 0-5° C. for one hour and then left to stand overnight at room temperature. It is poured into a water/ice mixture and extracted with methylene chloride, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure.
- a mixture of 1.17 g (0.0054 mol) of the product of the previous step and 0.62 ml (0.0072 mol) of bromoacetyl bromide is cooled to 0-5° C. and 0.81 g (0.006 mol) of aluminum trichioride is added.
- the mixture is stirred at 0-5° C. for one hour and then at room temperature for 4 hours. It is poured onto ice, the two phases are separated, the organic phase is washed with water and dried and the solvent is evaporated off under reduced pressure. The residue is dissolved in 2.9 ml of trifluoroacetic acid, 3.1 ml (0.0267 mol) of triethyl-silane are added and the mixture is heated at 80° C. for 5 hours. It is poured into an aqueous sodium bicarbonate solution and extracted with ethyl ether.
- the resulting oil is purified by chromatography on a silica gel column using a 7/3 cyclohexane/ethyl acetate mixture as the eluent.
- Two products of similar Rf are isolated.
- the product with the highest Rf corresponds to 1-[2-(3-methyl-4-pentylphenyl)ethyl ]-4(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine.
- the oxalate is prepared in acetone to give 0.12 g of product. M.p. 140-143° C.
- the product with the lowest Rf corresponds to the isomer 1-[2-(4-methyl-3-pentylphenyl)ethyl]4(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine.
- the oxalate is prepared in acetone.
- the product is crystallized from acetone to give 0.08 g of product. M.p. 167-169° C.
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9615335 | 1996-12-13 | ||
FR9615335A FR2757160B1 (fr) | 1996-12-13 | 1996-12-13 | 1-phenylalkyl-1,2,3,6-tetrahydropyridines |
PCT/FR1997/002286 WO1998025903A1 (fr) | 1996-12-13 | 1997-12-12 | 1-phenylalkyl-1,2,3,6-tetrahydropyridines pour le traitement de la maladie d'alzheimer |
Publications (1)
Publication Number | Publication Date |
---|---|
US6034090A true US6034090A (en) | 2000-03-07 |
Family
ID=9498641
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/331,006 Expired - Fee Related US6034090A (en) | 1996-12-13 | 1997-12-12 | 1-Phenylalkyl-1,2,3,6-tetrahydropyridines for treating Alzheimer's disease |
Country Status (32)
Country | Link |
---|---|
US (1) | US6034090A (sr) |
EP (1) | EP0950048B1 (sr) |
JP (1) | JP3881384B2 (sr) |
KR (1) | KR100560358B1 (sr) |
CN (1) | CN1129579C (sr) |
AT (1) | ATE202561T1 (sr) |
AU (1) | AU730143B2 (sr) |
BR (1) | BR9713916A (sr) |
CA (1) | CA2275353C (sr) |
CY (1) | CY2274B1 (sr) |
CZ (1) | CZ289789B6 (sr) |
DE (1) | DE69705429T2 (sr) |
DK (1) | DK0950048T3 (sr) |
EE (1) | EE03763B1 (sr) |
ES (1) | ES2160977T3 (sr) |
FR (1) | FR2757160B1 (sr) |
GR (1) | GR3036643T3 (sr) |
HK (1) | HK1023997A1 (sr) |
HU (1) | HU224347B1 (sr) |
IL (1) | IL130003A (sr) |
IS (1) | IS1969B (sr) |
NO (1) | NO312720B1 (sr) |
NZ (1) | NZ336033A (sr) |
PL (1) | PL190789B1 (sr) |
PT (1) | PT950048E (sr) |
RS (1) | RS49807B (sr) |
RU (1) | RU2189975C2 (sr) |
SI (1) | SI0950048T1 (sr) |
SK (1) | SK283331B6 (sr) |
TR (1) | TR199901291T2 (sr) |
UA (1) | UA52707C2 (sr) |
WO (1) | WO1998025903A1 (sr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6342505B1 (en) * | 1997-05-28 | 2002-01-29 | Sanofi-Synthelabo | Use of 4-substituted tetrahydropyridines for making medicines acting on TGF-β1 |
US20050004132A1 (en) * | 2001-11-19 | 2005-01-06 | Marco Baroni | Nitrogenous tetrahydropyridyl-alkyl-heterocycles with tnf activity |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA81749C2 (uk) * | 2001-10-04 | 2008-02-11 | Х. Луннбек А/С | Фенілпіперазинові похідні як інгібітори зворотного захоплення серотоніну |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3954871A (en) * | 1969-10-01 | 1976-05-04 | Continental Pharma | 1-(4-Alkylthiopheny)-2-substituted amino-alcohols and their salts |
US5109005A (en) * | 1989-08-07 | 1992-04-28 | Sanofi | Trifluoromethylphenyltetrahydropyridines for the treatment and/or prophylaxis of intestinal motility disorders |
US5229389A (en) * | 1990-05-22 | 1993-07-20 | Sanofi | Method for evaluating neuronal activity of a drug |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE34545B1 (en) * | 1969-10-01 | 1975-06-11 | Continental Pharma | Amino-alcohols,their salts and process for preparing the same |
HU211019B (en) * | 1991-12-02 | 1995-09-28 | Richter Gedeon Vegyeszet | Process for producing new 1,2,3,6-tetrahydropyridine and piperidine derivatives substituted with n-(hydroxylalkyl) group and compositions comprising such compounds |
-
1996
- 1996-12-13 FR FR9615335A patent/FR2757160B1/fr not_active Expired - Fee Related
-
1997
- 1997-12-12 SK SK786-99A patent/SK283331B6/sk unknown
- 1997-12-12 RU RU99115083/04A patent/RU2189975C2/ru not_active IP Right Cessation
- 1997-12-12 BR BR9713916-5A patent/BR9713916A/pt not_active Application Discontinuation
- 1997-12-12 ES ES97951323T patent/ES2160977T3/es not_active Expired - Lifetime
- 1997-12-12 HU HU0001185A patent/HU224347B1/hu not_active IP Right Cessation
- 1997-12-12 DK DK97951323T patent/DK0950048T3/da active
- 1997-12-12 CA CA002275353A patent/CA2275353C/en not_active Expired - Fee Related
- 1997-12-12 IL IL13000397A patent/IL130003A/en not_active IP Right Cessation
- 1997-12-12 CZ CZ19992113A patent/CZ289789B6/cs not_active IP Right Cessation
- 1997-12-12 US US09/331,006 patent/US6034090A/en not_active Expired - Fee Related
- 1997-12-12 AT AT97951323T patent/ATE202561T1/de not_active IP Right Cessation
- 1997-12-12 KR KR1019997005203A patent/KR100560358B1/ko not_active IP Right Cessation
- 1997-12-12 UA UA99063286A patent/UA52707C2/uk unknown
- 1997-12-12 AU AU54893/98A patent/AU730143B2/en not_active Ceased
- 1997-12-12 EE EEP199900237A patent/EE03763B1/xx not_active IP Right Cessation
- 1997-12-12 SI SI9730187T patent/SI0950048T1/xx unknown
- 1997-12-12 PL PL334071A patent/PL190789B1/pl unknown
- 1997-12-12 CN CN97180581A patent/CN1129579C/zh not_active Expired - Fee Related
- 1997-12-12 RS YUP-243/99A patent/RS49807B/sr unknown
- 1997-12-12 JP JP52632098A patent/JP3881384B2/ja not_active Expired - Fee Related
- 1997-12-12 DE DE69705429T patent/DE69705429T2/de not_active Expired - Fee Related
- 1997-12-12 PT PT97951323T patent/PT950048E/pt unknown
- 1997-12-12 EP EP97951323A patent/EP0950048B1/fr not_active Expired - Lifetime
- 1997-12-12 TR TR1999/01291T patent/TR199901291T2/xx unknown
- 1997-12-12 NZ NZ336033A patent/NZ336033A/xx unknown
- 1997-12-12 WO PCT/FR1997/002286 patent/WO1998025903A1/fr not_active Application Discontinuation
-
1999
- 1999-06-10 IS IS5075A patent/IS1969B/is unknown
- 1999-06-11 NO NO19992869A patent/NO312720B1/no unknown
-
2000
- 2000-05-30 HK HK00103181A patent/HK1023997A1/xx not_active IP Right Cessation
-
2001
- 2001-09-18 GR GR20010401501T patent/GR3036643T3/el not_active IP Right Cessation
-
2002
- 2002-05-15 CY CY0200027A patent/CY2274B1/xx unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3954871A (en) * | 1969-10-01 | 1976-05-04 | Continental Pharma | 1-(4-Alkylthiopheny)-2-substituted amino-alcohols and their salts |
US5109005A (en) * | 1989-08-07 | 1992-04-28 | Sanofi | Trifluoromethylphenyltetrahydropyridines for the treatment and/or prophylaxis of intestinal motility disorders |
US5229389A (en) * | 1990-05-22 | 1993-07-20 | Sanofi | Method for evaluating neuronal activity of a drug |
US5270320A (en) * | 1990-05-22 | 1993-12-14 | Elf Sanofi | Use of a 1-(2-naphthylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine for the manufacture of a medicament for the treatment of cerebral and neuronal diseases |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6342505B1 (en) * | 1997-05-28 | 2002-01-29 | Sanofi-Synthelabo | Use of 4-substituted tetrahydropyridines for making medicines acting on TGF-β1 |
US6693118B2 (en) * | 1997-05-28 | 2004-02-17 | Sanofi-Synthelabo | Use of 4-substituted tetrahydropyridines for the manufacture of medicaments acting upon TGF-β1 |
US20040157868A1 (en) * | 1997-05-28 | 2004-08-12 | Francoise Bono-Combie | Use of 4-substituted tetrahydropyridines for the manufacture of medicaments acting upon TGF-beta 1 |
US7320982B2 (en) | 1997-05-28 | 2008-01-22 | Sanofi-Aventis | Use of 4-substituted tetrahydropyridines for the manufacture of medicaments acting upon TGF-β 1 |
US20050004132A1 (en) * | 2001-11-19 | 2005-01-06 | Marco Baroni | Nitrogenous tetrahydropyridyl-alkyl-heterocycles with tnf activity |
US7211578B2 (en) | 2001-11-19 | 2007-05-01 | Sanofi-Aventis | Nitrogenous tetrahydropyridyl-alkyl-heterocycles with TNF activity |
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Owner name: SANOFI, FRANCE Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BARONI, MARCO;CARDAMONE, ROSANNA;FOURNIER, JACQUELINE;AND OTHERS;REEL/FRAME:010123/0678 Effective date: 19990607 |
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